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Allosteric modulation of the dopamine D2 receptor by Pro-Leu-Gly-NH2 peptidomimetics constrained in either a polyproline II helix or a type II beta-turn conformation.

Abstract：

:Type II beta-turn mimics and polyproline II helix mimics based upon diastereoisomeric 5.6.5 spiro bicyclic scaffolds have provided two pairs of Pro-Leu-Gly-NH(2) (PLG) peptidomimetics with contrasting dopamine receptor modulating activities. Compounds 1a and 3a were found to be positive allosteric modulators of the dopamine receptor, while the corresponding diastereoisomeric compounds 1b and 3b provided the first PLG peptidomimetics with the ability to decrease the binding of agonists to the dopamine receptor. The positive allosteric modulating activity of 3a supported the hypothesis that a polyproline II helix conformation is the bioactive conformation for the PLG analogue Pro-Pro-Pro-NH(2). The results also show that a change in the bridgehead chirality of the 5.6.5 scaffold brings about opposite effects in terms of the modulation of the dopamine receptor.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Raghavan B,Skoblenick KJ,Bhagwanth S,Argintaru N,Mishra RK,Johnson RL

doi

10.1021/jm801575w

subject

Has Abstract

pub_date

2009-04-09 00:00:00

pages

2043-51

issue

7

eissn

0022-2623

issn

1520-4804

journal_volume

52

pub_type

杂志文章

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